Quantitative benefit-risk analysis based on linked PKPD and health outcome modelling
Dyfrig Hughes
Centre for Health Economics and Medicines Evaluation, Bangor University
Objectives: Health outcomes modelling, conventionally used in health technology assessment, is based on disease progression models with the probabilities of benefit and harm for health states based on epidemiological and clinical trial evidence, and the health state preferences based on utility estimates. During early phases of clinical drug development, and where randomised controlled trials may not be possible, outputs from PKPD models may serve as inputs to health outcome models to inform the balance of harms and benefits based on the quality-adjusted life-year (QALY). Here, a comparison is made of the net clinical benefits of genotype-guided warfarin with both standard, clinically-dosed warfarin and three new oral anticoagulants (dabigatran, rivaroxaban and apixaban).
Methods: A clinical trial simulation based on a PKPD model of S-warfarin was used to predict differences in time within therapeutic range (TTR) between genotype guided and clinically dosed warfarin. A meta-analysis of trials linking TTR with outcomes was conducted to obtain relative risks of different clinical events. A discrete event simulation model representative of the AF population in the UK was used to extrapolate event risks to a lifetime horizon. Modelled outputs included clinical outcomes and QALYs.
Results: In the base case analysis, genotype guided-warfarin, rivaroxaban, apixaban and dabigatran extended life by 0.003, 1.11, 2.06 and 1.47 months, respectively, compared with clinical algorithm dosed warfarin. The corresponding incremental net benefits were 0.0031 (95% central range [CR] -0.1649 to 0.1327), 0.0957 (95% CR -0.0510 to 0.2431), 0.1298 (95% CR -0.0290 to 0.2638) and 0.1065 (95% CR -0.0493 to 0.2489) QALYs. In pairwise comparisons, using clinical algorithm dosed warfarin as the comparator, genotype guided warfarin, rivaroxaban, apixaban and dabigatran were associated with a positive incremental net health benefit in 57%, 83%, 90% and 85% of the simulations respectively.
Conclusion: Clinical trial simulations based on pharmacological models offer a new way to obtain estimates of net benefit in circumstances where trial data are not available. Based on our simulations, apixaban appears to be associated with the highest net benefit.
